Modern chemotherapy seeks to reduce the toxicity, to prolong the duration of action and to increase the selectivity of many medicaments, that is to say generally to increase the therapeutic index of the active principles. To achieve these objectives, recourse is had particularly to the use of polymeric materials controlling the release of the active principle.
At the present time there exist polymeric materials capable of ensuring control of the speed of release and the duration of action of medicaments. These systems were developed initially for contraception with steroid hormones. They are, until now, used for a wide range of active principles, both micro- and macromolecular types.
More precisely, the present invention relates to the incorporation of antimalaria agents in polymeric biomaterials by microencapsulation.
Microencapsulation groups all of the techniques enabling the obtaining of individualized particles whose size ranges between 1 and 1250 .mu.m.
The microparticles so obtained may be divided into two groups:
microcapsules, spherical particles constituted by a solid jacket containing a liquid, solid or pasty substance. Each microcapsule constitutes a reservoir system proper;
microspheres, particles, also spherical but constituted by a continuous network of support material in which the substance to be encapsulated is dispersed, in the molecular or particulate state. This structure, homogeneous or heterogeneous as the case may be, constitute a matrix system.
Antimalarial agents concerned by the present invention have been described in patent applications FR 87 04079 and BE 200041. They are primaquine and its derivatives such as amino acid-primaquine derivatives, targeted macromolecular conjugates, such as primaquine bonded to galactosylated albumin through a tetrapeptide arm which permits the release of an active form of primaquine at the level of the lysosomes of the targeted cells. These antimalarial agents seek to combat the hepatocyte forms of malaria.
A difficulty of the inventions in the field which interests us is the need to determine the polymers having properties defined according to the type of active principle to be incorporated. It is appropriate also to determine for a given drug type the speed of release and the charge ratio ensuring optimum therapeutic coverage for a selected period.
In the same way, the technique of incorporation depends on the polymer-medicament couple particularly the existence of a solvent common to the partners, the existence of thermal properties of the latter, their miscibility, etc. In addition, this incorporation must not alter the properties of the active principle.
There exist a wide variety of monomers which can be polymerized by different methods to form macromolecular chains. By modifying the nature of the polymers and their mode of linkage, macromolecular chemistry can hence create a wide range of materials. In a biomedical context, it is crucial for the polymers used to be biocompatible, hemocompatible and/or biodegradable, the choice of polymers being also in part dictated by the way of administration.
Considering that malaria is localized in underdeveloped countries where the facilities, both medical and paramedical, are extremely limited, it is appropriate to envisage the development of an injectable galenic form whose administration is the simplest.
One of the objects of the present invention is therefore the production of injectable microparticulate forms enabling the release kinetics to be modulated by means of polymeric materials for a series of molecules active against malaria.
Medicaments absorbed orally (pills, tablets, microparticles in a capsule, etc.) may be coated by a non-biodegradable filmogenic polymer, since it will be eliminated through the tractus after being released at the level of the stomach or at the entry of the intestine. On the other hand, if injectable forms are envisaged, the polymers must show particular properties, especially of biodegradability.